Project Summary/Abstract Fragment-based drug discovery (FBDD) is a widely used method in the pharmaceutical industry for the de novo design of molecules that target new drug candidates. Protein x-ray crystallography (PX) is the gold standard for determining the exact 3D location and orientation of a given fragment bound to a drug target. However, crystallography is expensive and inefficient for screening a large fragment library due to significant bottlenecks in crystallization, crystal soaking with fragments, crystal harvesting, X-ray data collection, structure determination and analysis. Complementary techniques are often used to prescreen for fragments that bind and PX is then used in a second step to determine the exact binding pose of each fragment. Accelero Biostructures is developing an efficient one-step PX-based fragment library-screening platform that can revolutionize the field by dramatically increasing the efficiency and reducing the cost of developing novel lead molecules for preclinical testing. Our Phase I plan is to evaluate a high-density crystallization grid, which will dramatically increase efficiency of target-fragment co-crystallization, crystal soaking with fragments and synchrotron-based data collection. Our Phase II plan will include a complete integration of this technology into our overall platform. Throughout we will use a previously ?non-druggable? target implicated in various cancers as proof-of-concept. Our plans align well with NCATS SBIR's topics of interest ?Tools and technologies to enable assaying of compound activity on currently ?non-druggable? targets? and ?Co-crystallization high- throughput screening techniques?.